tbuckley/cabot-search huggingface dataset:
PB1894: MIR-199A EXPRESSION PROFILES IN CHRONIC MYELOID LEUKEMIA: A PRELIMINARY STUDY
Authors: R. Frikha, I. Belguith, K. Leila
Journal: HemaSphere (2022)

Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. Up to date, although there is a certain number of reports on microRNA expression features, the expression and function of miR-199a in chronic myeloid leukemia remain to be investigated. Aims: We aimed to investigate miR-199a expression in CML patients and correlate with minimal residual disease (MRD). Methods: RT-PCR was performed to measure the expression level of miR-199a. Quantitative assessment of the BCR-ABL transcript was performed using the Cepheid Xpert BCR-ABL ultra-assay. Results: This study was conducted in 12 CML patients treated with TKI therapy. MiR-199a is highly expressed in CML patients mainly with a deeper molecular response (Ratio=33.36 vs 5.94 for DMR and MMR respectively). Summary/Conclusion: Despite the limit of our study, it underscores the importance of MiR-199a expression, as potential marker of optimal molecular evolution in patients under TKI therapy. Data from a larger number of patients are needed to reveal the clinical relevancy of MiR-199a expression in CML Tunisian patients.
Adaptive Dynamic Therapy and Survivorship for Operable Pancreatic Cancer
Authors: Samer AlMasri, Mazen Zenati, Abdulrahman Hammad, Ibrahim Nassour, Hao Liu, Melissa E. Hogg, Herbert J. Zeh, Brian Boone, Nathan Bahary, Aatur D. Singhi, Kenneth K. Lee, Alessandro Paniccia, Amer H. Zureikat
Journal: JAMA Network Open (2022)

Neoadjuvant therapy is increasingly used in localized pancreatic carcinoma, and survival is correlated with carbohydrate antigen 19-9 (CA19-9) levels and histopathologic response following neoadjuvant therapy. With several regimens now available, the choice of chemotherapy could be best dictated by response to neoadjuvant therapy (as measured by CA19-9 levels and/or pathologic response), a strategy defined herein as adaptive dynamic therapy.
P1407: CDK6 IN HEMATOPOIETIC STEM CELLS: MORE THAN A CELL CYCLE KINASE
Authors: I. Mayer, E. Doma, M. Prchal-Murphy, T. Klampfl, K. Kollmann, V. Sexl
Journal: HemaSphere (2022)

Background: Cell cycle kinase CDK6 acts as a transcriptional regulator and links cell cycle progression to differentiation and cellular homeostasis. CDK6 has been implicated in the initiation and progression of lymphoid and myeloid malignancies and regulates the balance of long-term hematopoietic stem cell (LT-HSC) dormancy and activation. CDK6 acts in a kinase-dependent and kinase-independent way to regulate haematopoiesis. Aims: As CDK4/6 inhibitors have entered the clinics, we aim at understanding and dissecting kinase-dependent and independent-functions of CDK6 in adult HSCs with application of different stress conditions. Methods: To investigate kinase-independent effects of CDK6 in HSCs, we made use of a mouse model harbouring a kinase inactivated mutant of CDK6 (Cdk6KM/KM). We performed in vivo serial transplantation and homing assays to study HSC re-population capacity. Low-input RNA-Seq of LT-HSCs after the 2nd serial transplantation round was used to understand transcriptional effects. Stressed haematopoiesis was further induced by chemical treatment with polyI:C. Results:Cdk6-/- HSCs are impaired in their ability to re-populate. This was not the case for Cdk6KM/KM hematopoietic cells evidenced by re-plating assays in vitro and serial transplantation settings in vivo. Cdk6KM/KM derived LT-HSCs maintain a stem-cell signature and express genes indicative for HSC dormancy at high levels compared to wild type LT-HSCs. Transcriptional analysis pointed to an altered and improved homing of Cdk6KM/KM LT-HSCs, which was confirmed in homing assays in vivo. This indicates a repressive role of CDK6 in stem cell homing. Upon polyI:C treatment, Cdk6KM/KM mice reacted with decreased stimulation as more Lin-Sca-1+c-kit+ (LSK) cells were residing in the bone marrow. Summary/Conclusion: Our data uncovers kinase-dependent and kinase-independent functions of CDK6 for HSC self-renewal and homing. Whereas serial transplantation settings and homing depend on kinase-inactive CDK6, poly-I:C treatment relies on kinase-activity.
PB1900: COVID-19 IMPACT ON CHRONIC MYELOID LEUKEMIA PATIENTS
Authors: S.-M. Galdean, R. Arbore, R. Ababei, D. Dragancea, R. A. Tomai, A. Trifa, S. Pasca, D. M. Dima
Journal: HemaSphere (2022)

Background: The management of CML (chronic myeloid leukemia) patients in COVID-19 era can be a challenge. CML patients are prone to severe infections and an increased mortality risk. There is an unmet need of clear and updated information in CML and COVID-19. Aims: We present our department’s experience on COVID-19 prevalence and severity in a cohort of CML patients diagnosed and treated at „ Prof. Ion Chiricuta” Oncology Institute, Hematology department. We report the SARS-CoV-2 vaccination rate and the vaccine’s adverse events. Methods: We analyzed the data on 286 CML patients, from our data base. 51 patients gave information on COVID-19 and vaccintaion status, through phone interview. Statistical data were obtained using R 3.5.1 software. Fisher test was used for contingent tables. Standard normal distribution was obtained using Shapiro-Wilk’s test. P value under 0.05 was considered statistically significant. Results: The patients were diagnosed with CML from 1996 to 2020. Median age at diagnosis was 48 and 54.9% were males. 62.7% patients had a low Sokal score, 29.4% intermediare Sokal score, 3.9% high Sokal score, respectively 80% patients had a low Eutos score. 74.5% patients were treated with Imatinib, 49.01% with Dasatinib, 41.1% with Nilotinib and 7.8% with Ponatinib, and 5.8% with Bosutinib. MMR was obtained in 84.3% patients, CHR in 11.7% and 3.9% patients lost their hematologic response. COVID-19 diagnosis was established by RT-PCR/ rapid antigen test or specific symptoms in 10 patients, during February and May 2021. 24 patients received SARS-CoV-2 vaccination in January to August 2021. Among COVID-19 patients, 30% discontinued on TKI treatment during COVID-19. The only parameter correlating with COVID-19 risk was the Hb value at diagnosis. Among vaccinated patients, 7 presented adverse events: 3 had local pain, 3 fever and myalgia, 1 digestive symptomes. There was no relation of vaccine adverse events and hematologic parameters at diagnosis or TKI treatment. Image:Summary/Conclusion: COVID-19 prevalence in CML patients is 0.9%, similare to the general population (0.1%). In România, the anti-COVID19 vaccination rate with complete doses, at current moment is 27.5%, and in our CML patient cohort the vaccination rate was 47%. The safety profile of vaccine is similar for CML patients and general population. The COVID-19 risk is not higher in CML patients. TKI treatment does not negatively influence the COVID-19 risk or response to vaccine. NCCN, ESMO and local guidelines reccommend for CML patients to vaccinate for SARS-CoV-2.
PB2082: POPULATION-WIDE PATTERNS OF CARE IN MANTLE CELL LYMPHOMA IN AUSTRALIA: AN ANALYSIS OF THE PHARMACEUTICAL BENEFITS SCHEME DATASET
Authors: C. Tam, F.-L. Zhao, T. Liu, R. Gauba, S. C. Li, B. Tang
Journal: HemaSphere (2022)

Background: The treatment landscape in patients with mantle cell lymphoma (MCL) is changing with the introduction of Bruton’s tyrosine kinase inhibitors (BTKis) and bendamustine in Australia. Aims: We sought to analyze the practice impact of the introduction of publicly funded novel agents in MCL. The objective of this study was to describe the evolving treatment patterns of Australian patients with MCL over the last 10 years using population-wide prescription records. Methods: Patients who initiated a treatment for MCL between 01/01/2011 and 07/31/2021 were extracted from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset, which includes the dispensing records for 10% of the Australian population. This dataset captures all publicly funded treatments in Australia. The index date was defined as the commencement of any drug for MCL. First-line (1L) therapy was defined as the first treatments prescribed for MCL. A patient was defined as relapsed/refractory (R/R) if they had commenced a drug which was in a different therapeutic category, or if they re-started the same regimen after a gap of more than 180 days. Descriptive analyses were conducted to examine the use of treatment regimens for the overall 10-year population by line of therapy. Analyses by calendar year were also performed to assess the changes in the treatment patterns. Results: Overall, 241 patients with MCL were identified over the study period. The majority of patients were male (68.4%), age > 60 years (84.9%), and most being aged 70-79 years (42.1% of total). Many patients were receiving comedications at baseline, including antihypertensives (44.1%), anticoagulants (14.5%), and/or antipsychotics or antidepressants (12.5%). In the overall population (2011-2021), the majority of patients had received 1L treatment with bendamustine-rituximab (BR, 53.9%), rituximab plus other regimens (27.6%), or rituximab monotherapy (11.2%). The most commonly used regimens in R/R patients at any subsequent episode of treatment included BTKi (66.3%), rituximab monotherapy (52.8%) or rituximab plus other regimens (31.5%). A trend in adoption of novel agents was observed throughout the years following their PBS listing. Analysis by calendar year showed that from 2011 to 2020 for 1L therapy, the use of BR increased from 0% to 50% and use of rituximab-containing regimen except BR decreased from 100% to 16.7%; use of BTKi increased in R/R patients from 0% to 74.7%. Summary/Conclusion: MCL treatment patterns have significantly changed in Australia since the introduction of BTKis and bendamustine-containing regimens. The use of rituximab-containing regimens except BR in 1L MCL has decreased and use of BTKis in R/R patients has increased.
PB2234: HEALTH LITERACY LEVEL ASSOCIATED WITH THALASSEMIA AMONG TUNISIAN’S YOUTH AND PROSPECTS FOR PRIMARY PREVENTION
Authors: F. Maaoui, I. Moumni, F. Arboix-Calas, I. Safra, S. Mnif
Journal: HemaSphere (2022)

Background: Thalassemia remains a public health problem in Tunisia. The difficulties in setting up a prevention program can be explained in part by negative social representations and the general public’s ignorance of this disease. Aims: This study examined the health literacy (HL) of Tunisian secondary school students regarding thalassemia as well as their emotional and behavioral attitudes towards this disease and preventive measures. Methods: This is a quantitative study; a cross-sectional survey was conducted among Tunisian youths (n = 182; male 23,3 %, female 76,7 %). Data collection took place in two public secondary schools. Students aged 17 to 19 completed a paper and pencil questionnaire and described their knowledge level about Thalassemia, their affective and behavioral attitudes as well as their estimates of hereditary transmission risks and usefulness of prevention measures. Statistical software (SPSS, v.25.0) was used to analyze the data. Results: The results indicate low HL scores concerning Thalassemia. Lack of knowledge and confusion about the cause, symptoms, and diagnosis of Thalassemia is a common finding at all school levels surveyed. 48,9 % has not identified the hereditary nature of diseases and confuse it with dietary iron anemia 30,7%. Although 70,5% of respondents recognized severe anemia as a symptom however, 57,4% did not link jaundice to thalassemia, almost 30% said this disease causes rash, fever, dry cough and sore throat. The results show low levels in relation with assessment of the hereditary transmission risks on the one hand and the prenuptial screening usefulness on the other hand. 24,4% do not consider it necessary to inform their partner of their carrier status. 45% do not see the benefit of genetic counseling before marriage and prenatal diagnosis even if the family of one of the two partners has a history with disease. Summary/Conclusion: Primary prevention of thalassemia depends on a comprehensive strategy of promotion and health education for Tunisian’s youth. This survey reveals the difficulties of youths to consider the risks of hereditary transmission of thalassemia and to understand the importance of screening and genetic counseling. These results can be explained by the deficit of communication about disease severity and the lack of adequate educational content in Life Sciences programs.
PB1952: EFFECTS OF KNOCKDOWN OF NUPR1 GENE ON THE PROLIFERATION AND APOPTOSIS OF MULTIPLE MYELOMA CELLS AND ITS MECHANISM
Authors: C. Zeng, C. Xiao, Y. Nan, L. Zhang, Y. Xiang, Y. Liu
Journal: HemaSphere (2022)

Background: Multiple myeloma is easy to relapse and incurable. It is necessary to further explore the pathogenesis to find new drugs Aims: To construct nuclear protein 1-short hairpin RNA (NUPR1-shRNA) expressing lentiviral vector targeting NUPR1 gene and investigate the effect of NUPR1 gene silencing on the proliferation and apoptosis of human multiple myeloma U266 and RPMI8226 cells and its related mechanisms. Methods: The normal human bone cells were used as control and the mRNA expression level of NUPR1 in multiple myeloma cell lines (U266 and RPMI8226) and MM patient specimens were detected by quantitative real-time PCR (qRT-PCR). Then the NUPR1 gene target shRNA plasmid was constructed and screen for the best target for transfected into U266 and RPMI8226 cells. The transfection efficiency was detected by flow cytometry. The interference effect of NUPR1 gene was detected by qRT-PCR and Western blotting. The cell proliferation was analyzed by CCK-8 assay. The cell apoptosis and cell cycle were determined by flow cytometry. Quantitative RT-PCR and Western blot were used to detect the expression of proliferation and apoptosis-related genes and proteins. Results: The mRNA expression levels of NUPR1 in MM cell lines (U266 and RPMI8226) and MM patient specimens were higher than that in normal bone cells. NUPR1-shRNA-expressing lentiviral vector was successfully constructed, and flow cytometry results shows that the transfection efficiency of both cell line reached over 80%. Quantitative RT-PCR and Western blot showed that NUPR1-shRNA2 lentiviral vector most effectively and as the best target. With NUPR1 gene interference, cell proliferation were significantly inhibited in U266 and RPMI8226 cells infected with the NUPR1-shRNA lentiviral compared with the control group. Compared with the control group, the apoptosis rate of U266 and RPMI8226 in shNUPR1 group were significantly increased (P<0.05). Flow cytometer indicated that the U266 and RPMI8226 cells in shRNA group were arrested in G0/G1 phase (P < 0.01). Compared with the control group, qRT-PCR and Western blot showed that the levels of Bcl-2 and PCNA were significantly down-regulated, and the level of PTEN was significantly increased in shNUPR1 group. Meanwhile, the expression of cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9 protein were significantly higher in U266 and RPMI8226 cells infected with the NUPR1-shRNA lentiviral compared with the control group. Summary/Conclusion: The mRNA expression levels of NUPR1 in U266 and RPMI8226 cells were higher than that in normal bone cells, and the NUPR1-shRNA-expressing lentiviral vector was successfully constructed. Down-regulate the expression of NUPR1 in U266 and RPMI8226 cells can inhibit cell proliferation and promote its apoptosis.
P1651: HDAC3 RS2530223 IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY AND SEVERITY OF PRIMARY IMMUNE THROMBOCYTOPENIA
Authors: S. Wang
Journal: HemaSphere (2022)

Background: Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder characterized by a low platelet count and increased risk of bleeding. We previously reported that low-dose chidamide, a histone deacetylase (HDAC) inhibitor, restores immune tolerance in patients with ITP. Aims: To evaluate the association of a single nucleotide polymorphism (SNP) rs2530223 in the HDAC3 gene with susceptibility to ITP and its clinical features. Methods: Patients with ITP and age-matched healthy participants were recruited for this case-control study. Accordingly, from September 2017 to February 2021, 209 patients, diagnosed with primary ITP according to the ITP international guidelines were recruited. The genotyping of the SNP of HDAC3 (rs2530223) was conducted by the time-of-flight mass spectrometry system. And SPSS software was used for statistical analyses. Results: Our results revealed that the T allele exhibited a 1.472-fold increased risk of ITP susceptibility (OR 1.472; 95% CI 1.100–1.969; p = 0.009), the TT genotype under the codominant and recessive models, and the TC/TT genotypes under the dominant model all revealed increased risk of ITP susceptibility (dominant OR 1.965; 95% CI: 1.046–3.656; p = 0.036; codominant OR 2.264; 95% CI 1.175–4.360; p = 0.015; and recessive OR 1.512; 95% CI 1.028–2.224; p = 0.036, respectively). Regarding platelet counts in ITP patients, we observed that the TC/TT genotypes exhibited a 3.932-fold increased risk for PLT <30×109/L (OR 3.932; 95% CI 1.426–10.842; p = 0.008). Image:Summary/Conclusion: This study indicates that HDAC3 rs2530223 may be an important genetic factor related to ITP susceptibility and platelet count in ITP patients, providing new perspectives on disease progression, new therapeutic targets, and severity prediction.
PB2073: LACK OF AGREEMENT ON EVENT-FREE SURVIVAL DEFINITION IN MARGINAL ZONE LYMPHOMA
Authors: C. Bommier, J. Lambert, G. Nowakowski, E. Zucca, C. Thieblemont
Journal: HemaSphere (2022)

Background: A recent systematic review reported that trials involving patients with marginal zone lymphoma (MZL) show marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials (1). Aims: The main objective of this study was to reach consensus, through a Delphi process, on the definitions of four time-to-event endpoints in MZL trials, by surveying clinicians and methodologists involved in the conduct of clinical trials including patients with MZL. Methods: We polled a panel of leading international experts involved in MZL trials, after the 2021 IELSG meeting, by means of self-administered sequential questionnaires. Of these 105 experts, 62 responded to the Round 1 questionnaire regarding the definitions of Progression-free survival (PFS), Event-free survival (EFS), Time-to-failure (TTF) and Time-to-next-treatment (TTNT). Afterwards we therefore focused the Round 2 and 3 questionnaires among principal investigators, coinvestigators and trial methodologists. Consensus was reached when there was a >80% agreement on all potential events (11 choices) of each endpoint. Results: Participants in our survey reached consensus on 3 of the 4 time-to-event endpoints definitions. Consensus was reached on the definitions of PFS and TTNT after Round 1, of TTF after Round 2 and was not reached for EFS after Round 3. Although experts agreed on the inclusion of the addition of new therapy as an event, the experts differed on the criterion of treatment discontinuation (53% vs 47%). Since there was no trend for or against this criterion, it was decided to stop the Delphi process at this point (see Figure). Image:Summary/Conclusion: The main interest of our study was to elicit investigators interest in the importance of consistently defining endpoints in MZL trials and to highlight that composite endpoints should not be encouraged. Fifteen years after the last consensus statement on time-to-event endpoints definitions issued in Lugano (2007), both the review of literature and survey of international investigators agree on the inconsistency of endpoints definitions used within the MZL community. Hopefully, revised standardized definitions of endpoints shall be provided at the upcoming International Conference on Malignant Lymphoma in 2023. (1) Bommier C, Ruggiu M, Monégier A, Zucca E, Thieblemont C, Lambert J. Systematic review reveals urgent need to homogenize endpoints choices and definitions in marginal zone lymphomas trials. Leukemia & Lymphoma. Published online February 24, 2022:1-12. doi:10.1080/10428194.2022.2032038
Abstract LB214: Discovery of EPIM-001, a tumor targeted engineered IL2 with biased IL2Rβ agonist activities
Authors: Kehao Zhao, Sam Hassan, Yan Chen, Jenna Nguyen, Ning Jiang, Gening Zhang, Irene Li, Ryan Feng
Journal: Cancer Research (2022)

Abstract Background: The cytokine Interleukin 2 (IL2) has been approved for cancer treatment. However, its application has been limited due to severe toxicities associated with its high concentration administration. These side effects are attributed to the strong binding of IL2 to its receptor IL2Rα which is enriched on regulatory T Cells and Lung epithelial cells. We have engineered IL2 to significantly reduce IL2Rα binding and enhance IL2Rβ binding. We further developed EPIM-001, a bi-functional IL2Rβ agonist and Anti-PDL1 biologic, aiming to treat a broad set of solid tumors with improved therapeutic index. Methods: We used mSCAFold࣪, a unique protein engineering platform to redefine and improve pharmacologic properties of the cytokine through structure-based rationally designed libraries and mRNA display selection. The optimal IL2 candidate with enhanced IL2Rβ and reduced IL2Rα binding was engineered with an internally discovered anti-PD-L1 antibody to generate EPIM-001, a bispecific IL2/PD-L1 biologic drug candidate. EPIM-001 was characterized in vitro for receptor binding activity, immune cell activation, proliferation, and tumor cell killing assays. In vivo efficacy was evaluated in xenograft humanized mouse models, and PK/PD and toxicity has been studied in Non-Human Primates (NHPs). Results: We have shown that EPIM-001 is a strong agonist of IL2Rβ, with significantly reduced binding to IL2Rα. It demonstrated much stronger CD8+ T cells and NK cell activation and proliferation compared WT-IL2, whilst only weaker activation and minimal proliferation with Tregs. In vitro cell killing assays showed that EPIM-001 promoted better immune cell killing of PD-L1 expressing target cells than WT IL2. In xenograft in vivo studies, EPIM-001 has shown significant tumor growth inhibition against the human lung cancer cell line H1975, which whilst expressing high levels of PD-L1, does not respond to PD-L1/PD-1 blockade. Furthermore, in the human breast cancer cell line MDA-MB-231, EPIM-001 showed stronger tumor growth inhibition compared to Keytruda. PK/PD and toxicity studies in NHPs showed that EPIM-001 is well tolerated. EPIM-001 greatly expanded CD8+ T cells, whilst having minimal effect on TRegs and Eosinophils associated with toxicity. Conclusions: EPIM-001 is a promising immune modulating drug candidate that selectively activates CD8+ T cells and NK Cells with strong anti-tumor activity and safe profile for both immune checkpoint sensitive and insensitive PD-L1 positive tumors. Citation Format: Kehao Zhao, Sam Hassan, Yan Chen, Jenna Nguyen, Ning Jiang, Gening Zhang, Irene Li, Ryan Feng. Discovery of EPIM-001, a tumor targeted engineered IL2 with biased IL2Rβ agonist activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB214.